Currently the prevalence of Multiple Myeloma (MM) is 63,000 people in the US with about 13,000 new cases per year. There are 360,000 cases of non-Hodgkin's lymphoma (NHL) in the United States and 550,000 worldwide, with about 56,000 cases diagnosed per annum and 23,000 deaths per annum (American Cancer Society, The SEER Cancer Statistics Review (CSR) web site, http://seer.cancer.gov/csr/1975—2002/). Twenty percent of these do not respond to current therapy. In terms of all NHL cases, 60% are aggressive, of which 50% do not respond to front line therapy. In addition, chronic lymphocytic leukemia (CLL) is the most common form of adult leukemia in the U.S. and in most of Western Europe. There are approximately 70,000 cases of CLL in the U.S., with 10,000 new cases diagnosed per annum (www.cancer.gov/cancertopics/types/leukemia). CLL patients have a poor survival prognosis with a five-year survival rate of 46%.
Mcl-1 is a key regulator of lymphoid cancers including multiple myeloma (MM) (Zhang B et al. (2002), Blood 99: 1885-1893), non-Hodgkin's lymphomas (Cho-Vega J H et. al (2004) Hum. Pathol. 35(9): 1095-100) and chronic lymphocytic leukemia (CLL) (Michaels J, et al. (2004), Oncogene 23: 4818-4827). Additionally, treatment of myeloma cells with the proteosome inhibitor Bortezomib (Velcade) has been shown to cause elevated Mcl-1 expression (Nencioni A, et al. (2005) Blood; 105(8):3255-62) and this is seen in some myeloma patients (Podar K et al. (2008) Oncogene 27(6):721-31). It is proposed that an Mcl-1 inhibitor would enhance the efficacy of Velcade treatment in MM patients.
Though Rituxan, which targets B-cell surface protein CD-20, has proven to be a valuable front line therapeutic for many NHL and CLL patients, resistance to this drug has been shown to correlate with elevated expression of B-cell lymphoma 2 (Bcl-2) or Myeloid Cell factor-1 (Mcl-1) proteins (Hanada et al. (1993) Blood 82: 1820-28; Bannerji et al. (2003) J. Clin. Oncol. 21(8): 1466-71). Notably, there is a high correlation of elevated Mcl-1 with non-responsiveness to chemotherapies in B-cells from CLL patients. (Kitada et al. (2002) Oncogene 21: 3459-74). Rituxan-resistant CLL cells also have a higher Mcl-1/Bax ratio than normal cells, while there is no significant correlation of the Bcl-2/Bax ratio. (Bannerji et al. (2003) supra).
Moreover, approximately 30% of diffuse large cell lymphomas (DLCLs) have increased Bcl-2 expression levels. This correlates with poor patient response to treatment with combination chemotherapy (Mounier et al. (2003) Blood 101: 4279-84). In follicular non-Hodgkin's lymphomas and plasma cell myeloma, Mcl-1 expression positively correlates with increasing grade of the disease (Cho-Vega et al. (2004) Hum. Pathol. 35(9): 1095-100).
The value of Bcl-2 as a target in anti-tumor therapy has been well established. The literature also reports on Mcl-1 as a target in treating NHL, CLL, and acute mylogenous leukemia (AML) (Derenne et al. (2002) Blood, 100: 194-99; Kitada et al. (2004) J. Nat. Canc. Inst. 96: 642-43; Petlickovski et al. (2005) Blood 105: 4820-28). Researchers have recognized that proteins in the Bcl-2 family regulate apoptosis and are key effectors of tumorigenesis (Reed (2002) Nat. Rev. Drug Discov. 1(2): 111-21). Bcl-2 promotes cell survival and normal cell growth and is expressed in many types of cells including lymphocytes, neurons and self-renewing cells, such as basal epithelial cells and hematopoietic progenitor cells in the bone marrow.
In many cancers, anti-apoptotic Bcl-2 proteins, such as Bcl-2 and Mcl-1, unfortunately block the sensitivity of tumor cells to cytostatic or apoptosis inducing drugs. These proteins are therefore targets for anti-tumor therapy. A recently described class of small molecules that inhibit Bcl-2 family proteins are the BH3 mimetic compounds (Nat. Reviews Drug Discovery vol 4: 399-409). These compounds function by inhibiting BH3 mediated protein/protein interactions among the Bcl-2 family proteins. Several studies have described BH3 mimetic small molecules that function as Bcl-2 inhibitors by blocking BH3 binding (reviewed in Reed. et al. (2005) Blood 106: 408-418). Compounds with BH3 mimic function include HA-14-1 (Wang et al. (2000) Proc. Natl. Acad. Sci. USA 97: 7124-9), Antimycin-A (Tzung et al. (2001) Nat. Cell. Biol. 3: 183-191), BH3I-1 and BH3I-2 (Degterev et al. (2001) Nat. Cell. Biol. 3: 173-82), and seven un-named compounds (Enyedy et al. (2001) J. Med Chem 44: 4313-24), as well as a series of terphenyl derivatives (Kutzki et al. (2002) J. Am. Chem. Soc. 124: 11838-9), and two new classes of molecules (Rosenberg et al. (2004) Anal. Biochem. (2004) 328: 131-8). More recently, a BH3 mimic compound has been tested in a mouse tumor model (Oltersdorf et al. (2005) Nature 435(7042): 677-81).
The promise for using BH3 mimetic compounds as anti-tumor therapeutics has been recognized, and is described in the literature; however, to date there are no conclusive reports from the clinic on the efficacy of any anti-cancer drugs with this mode of action. While pharmacological manipulation of the Bcl-2 family proteins is a feasible approach to achieving therapeutic benefit for cancer patients, the complexity of the network of proteins that comprise this family makes this prospect difficult. Therefore, with the large unmet medical need for treating hematological malignancies, new approaches to assessing and utilizing the detailed activity of the BH3 mimic molecules will have value in developing this class of therapeutics.